EP1042326B1 - Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents
Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Download PDFInfo
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- EP1042326B1 EP1042326B1 EP98962511A EP98962511A EP1042326B1 EP 1042326 B1 EP1042326 B1 EP 1042326B1 EP 98962511 A EP98962511 A EP 98962511A EP 98962511 A EP98962511 A EP 98962511A EP 1042326 B1 EP1042326 B1 EP 1042326B1
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- SMPZPKRDRQOOHT-UHFFFAOYSA-N acronycine Chemical class CN1C2=CC=CC=C2C(=O)C2=C1C(C=CC(C)(C)O1)=C1C=C2OC SMPZPKRDRQOOHT-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 233
- -1 hydroxy, mercapto Chemical class 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 16
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 201000011510 cancer Diseases 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000004385 trihaloalkyl group Chemical group 0.000 claims abstract description 3
- 230000009021 linear effect Effects 0.000 claims description 102
- 238000000034 method Methods 0.000 claims description 66
- 230000009471 action Effects 0.000 claims description 55
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 42
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 14
- 150000008064 anhydrides Chemical class 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 230000003287 optical effect Effects 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 7
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- LJOQGZACKSYWCH-LHHVKLHASA-N (s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol Chemical compound C1=C(OC)C=C2C([C@H](O)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 LJOQGZACKSYWCH-LHHVKLHASA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- LJOQGZACKSYWCH-UHFFFAOYSA-N dihydro quinine Natural products C1=C(OC)C=C2C(C(O)C3CC4CCN3CC4CC)=CC=NC2=C1 LJOQGZACKSYWCH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 235000021513 Cinchona Nutrition 0.000 claims description 3
- 241000157855 Cinchona Species 0.000 claims description 3
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229930013930 alkaloid Natural products 0.000 claims description 3
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000005833 cis-dihydroxylation reaction Methods 0.000 claims description 3
- 229960000811 hydroquinidine Drugs 0.000 claims description 3
- 229960004251 hydroquinine Drugs 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 239000012285 osmium tetroxide Substances 0.000 claims description 3
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 230000001603 reducing effect Effects 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- UOISCARHVYSQMT-UHFFFAOYSA-N 6-methoxy-3,3,14-trimethyl-7,14-dihydro-3h-benzo[b]pyrano-[3,2-h]acridin-7-one Chemical compound C1=CC=C2C=C(C(=O)C=3C(OC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 UOISCARHVYSQMT-UHFFFAOYSA-N 0.000 claims description 2
- JXXOCQYPRDOSKK-UHFFFAOYSA-N C1=CC=C2C=C(C(=O)C=3C(NCCCN(CC)CC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCCCN(CC)CC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 JXXOCQYPRDOSKK-UHFFFAOYSA-N 0.000 claims description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000004069 aziridinyl group Chemical group 0.000 claims description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- OASYWNFOHKQIGI-KAYWLYCHSA-N chembl80535 Chemical compound C1=CC=C2C=C(C(=O)C=3C(OC)=CC4=C([C@@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(C)O4)C=3N3C)C3=CC2=C1 OASYWNFOHKQIGI-KAYWLYCHSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 claims description 2
- KUMNEOGIHFCNQW-UHFFFAOYSA-N diphenyl phosphite Chemical compound C=1C=CC=CC=1OP([O-])OC1=CC=CC=C1 KUMNEOGIHFCNQW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 125000000466 oxiranyl group Chemical group 0.000 claims description 2
- 150000004965 peroxy acids Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229960001553 phloroglucinol Drugs 0.000 claims description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 3
- 239000005864 Sulphur Substances 0.000 claims 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims 2
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims 1
- 150000001351 alkyl iodides Chemical class 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 150000002431 hydrogen Chemical class 0.000 abstract 4
- 229940126601 medicinal product Drugs 0.000 abstract 1
- 239000000047 product Substances 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 239000012429 reaction media Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 0 *c1cc(O)cc(O)c1 Chemical compound *c1cc(O)cc(O)c1 0.000 description 6
- CBBVVMOWLMMAKH-UHFFFAOYSA-N 4,6,9-trioxa-21-azapentacyclo[11.8.0.02,10.03,7.015,20]henicosa-1(21),2,7,10,12,15,17,19-octaene-5,14-dione Chemical compound O1C(OC=2C1=C1C3=NC=4C=CC=CC=4C(C3=CC=C1OC=2)=O)=O CBBVVMOWLMMAKH-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZTKMNYDOFAYRAK-UHFFFAOYSA-N isoacronycine Natural products CN1C2=CC=CC=C2C(=O)C2=C1C=C1OC(C)(C)C=CC1=C2OC ZTKMNYDOFAYRAK-UHFFFAOYSA-N 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 229910001868 water Inorganic materials 0.000 description 5
- XFXOLBNQYFRSLQ-UHFFFAOYSA-N 3-amino-2-naphthoic acid Chemical class C1=CC=C2C=C(C(O)=O)C(N)=CC2=C1 XFXOLBNQYFRSLQ-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- ARMDKQIXBKWLLM-UHFFFAOYSA-N chromeno[5,6-b]quinoline-2,8-dione Chemical compound C1=C2C(=O)C=CC=C2N=C2C1=CC=C1OCC(=O)C=C12 ARMDKQIXBKWLLM-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- CNCFAAKEQPTIGL-UHFFFAOYSA-N (+/-)-1-amino-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1h-benzo[b]pyrano[3,2-h]acridin-7-one Chemical compound C1=CC=C2C=C(C(=O)C=3C(OC)=CC4=C(C(N)C(O)C(C)(C)O4)C=3N3C)C3=CC2=C1 CNCFAAKEQPTIGL-UHFFFAOYSA-N 0.000 description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- ZGKVRYOUJKEBAL-UHFFFAOYSA-N 2h-chromen-2-amine Chemical compound C1=CC=C2C=CC(N)OC2=C1 ZGKVRYOUJKEBAL-UHFFFAOYSA-N 0.000 description 2
- IZSSEDJITPJCLY-UHFFFAOYSA-N 4,6,9-trioxa-21-azapentacyclo[11.8.0.02,10.03,7.015,20]henicosa-1(21),2,7,10,12,15,17,19-octaen-14-one Chemical compound O1COC=2C1=C1C3=NC=4C=CC=CC=4C(C3=CC=C1OC=2)=O IZSSEDJITPJCLY-UHFFFAOYSA-N 0.000 description 2
- MSGKXWSKKCVRCB-UHFFFAOYSA-N 6-hydroxy-3,3-dimethyl-7,14-dihydro-3h-benzo[b]pyrano[3,2-h]acridin-7-one Chemical compound C1=CC=C2C=C(C(C3=C(O)C=C4OC(C=CC4=C3N3)(C)C)=O)C3=CC2=C1 MSGKXWSKKCVRCB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 150000008050 dialkyl sulfates Chemical class 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
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- MZDMCNTVMLWQKO-FIRIVFDPSA-N [(5R,6R)-6-acetyloxy-11-[3-(dimethylamino)propylamino]-2,7,7-trimethyl-13-oxo-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4(9),10,14,16,18,20-octaen-5-yl] acetate Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCCCN(C)C)=CC4=C([C@@H](OC(C)=O)[C@@H](OC(C)=O)C(C)(C)O4)C=3N3C)C3=CC2=C1 MZDMCNTVMLWQKO-FIRIVFDPSA-N 0.000 description 1
- YETTYOVGPJSYCO-IHLOFXLRSA-N [(5R,6S)-6-acetyloxy-11-[2-(dimethylamino)ethylamino]-2,7,7-trimethyl-13-oxo-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4(9),10,14,16,18,20-octaen-5-yl] acetate Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCCN(C)C)=CC4=C([C@@H](OC(C)=O)[C@H](OC(C)=O)C(C)(C)O4)C=3N3C)C3=CC2=C1 YETTYOVGPJSYCO-IHLOFXLRSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
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- QXDHGZCXAXLEMG-UHFFFAOYSA-N chembl102972 Chemical compound C1=CC=C2C=C(C(=O)C=3C(OC)=CC4=C(C(=O)C(O)C(C)(C)O4)C=3N3C)C3=CC2=C1 QXDHGZCXAXLEMG-UHFFFAOYSA-N 0.000 description 1
- OBIMMISNDPJVEJ-FQLXRVMXSA-N chembl311536 Chemical compound O([C@H]1C(C)(C)OC=2C=C(C=3C(=O)C4=CC5=CC=CC=C5C=C4N(C)C=3C=2[C@H]1O)OC)C(=O)C1=CC=CC=C1 OBIMMISNDPJVEJ-FQLXRVMXSA-N 0.000 description 1
- LJVDDWUFCWWFKF-FIRIVFDPSA-N chembl80690 Chemical compound O([C@H]1C(C)(C)OC=2C=C(C=3C(=O)C4=CC5=CC=CC=C5C=C4N(C)C=3C=2[C@H]1OC(C)=O)OC)C(=O)C1=CC=CC=C1 LJVDDWUFCWWFKF-FIRIVFDPSA-N 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
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- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
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- UGAFQZRQCNIUIB-UHFFFAOYSA-N methyl 2-[(2,7,7-trimethyl-13-oxo-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4(9),5,10,14,16,18,20-nonaen-11-yl)amino]acetate Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCC(=O)OC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 UGAFQZRQCNIUIB-UHFFFAOYSA-N 0.000 description 1
- VWHLFJZWZLIMIJ-UHFFFAOYSA-N methyl 4-[(2,7,7-trimethyl-13-oxo-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4(9),5,10,14,16,18,20-nonaen-11-yl)amino]butanoate Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCCCC(=O)OC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 VWHLFJZWZLIMIJ-UHFFFAOYSA-N 0.000 description 1
- WZOZIQQFEVSEQH-UHFFFAOYSA-N methyl 5-[(2,7,7-trimethyl-13-oxo-8-oxa-2-azapentacyclo[12.8.0.03,12.04,9.016,21]docosa-1(22),3(12),4(9),5,10,14,16,18,20-nonaen-11-yl)amino]pentanoate Chemical compound C1=CC=C2C=C(C(=O)C=3C(NCCCCC(=O)OC)=CC4=C(C=CC(C)(C)O4)C=3N3C)C3=CC2=C1 WZOZIQQFEVSEQH-UHFFFAOYSA-N 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- YPLIFKZBNCNJJN-UHFFFAOYSA-N n,n-bis(ethylamino)ethanamine Chemical compound CCNN(CC)NCC YPLIFKZBNCNJJN-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003000 phloroglucinols Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 150000003020 phtalazines Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- UVDNCIMDCLWPJJ-UHFFFAOYSA-N pyrano[2,3-c]acridin-7-one Chemical compound C1=COC2=CC=C3C(=O)C4=CC=CC=C4N=C3C2=C1 UVDNCIMDCLWPJJ-UHFFFAOYSA-N 0.000 description 1
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- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
Definitions
- the present invention relates to new acronycin derivatives, their process for preparation and pharmaceutical compositions containing them.
- Acronycin is an alkaloid with anti-tumor properties demonstrated in experimental models ( J. Pharmacol. Sci. 1966, 55 (8), 758-768). However, despite a broad spectrum of activity, the low solubility of acronycin limits its bioavailability and does not make it possible to envisage its use in a mode of administration of the injectable type.
- the compounds of the invention in addition to the fact that they are new, have properties of interesting solubilization and adapted to an administration of the products in forms liquids and also surprisingly exhibit in-vitro and in-vivo activity very higher than those observed so far.
- the new analogues, discovered by the Applicant thus have anti-tumor properties which make them particularly suitable for use in the treatment of cancers and in particular tumors solid.
- hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic acids, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane sulfonic, camphoric, etc ...
- non-limiting examples that may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.
- R 3 and R 4 preferred according to the invention are the linear or branched (C 1 -C 6 ) alkyl groups, with R 3 and R 4 identical or different.
- the preferred substituents R 2 according to the invention are the linear or branched (C 1 -C 6 ) alkoxy groups, or the amino groups optionally substituted by one or two substituents as defined above, and advantageously the amino groups substituted by a group of formula -R 9 -NR 7 R 8 with R 9 is as defined above, and R 7 , R 8 , identical or different, represent a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group.
- optical isomers, N-oxides, as well as, where appropriate, the addition salts with an acid or with a base, pharmaceutically acceptable, preferred compounds are an integral part of the invention.
- the compounds of formula (II), (III), (VI) and (VII) are either commercial compounds or are obtained according to conventional methods of organic synthesis and for the compounds of formula (VII) are obtained according to the conditions described in Chem. Ber . 1978, 191, 439.
- the condensation reaction between the compounds of formula (VI) and the compounds of formula (VII) is described in particular in the review Heterocycles, 1992, 34 (4), 799-806.
- the compounds of formula (I) exhibit particularly anti-tumor properties interesting. They have excellent in vitro cytotoxicity on cell lines, and a action on the cell cycle, and are active in vivo. In addition, these new compounds have shown to be much more active and potent than the reference compound, acronycin. They have, in addition, the property of being soluble, thus allowing administration by intravenous. The characteristic properties of these compounds allow their use in therapeutic as anti-tumor agents.
- the present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its optical isomers, N-oxides or one of its addition salts with a base or a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-toxic excipients or vehicles, pharmaceutically acceptable.
- compositions according to the invention it will be cited more particularly those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, and in particular simple or coated tablets, tablets sublingual, capsules, capsules, suppositories, creams, ointments, gels dermal, injectable or drinkable preparations, aerosols, eye drops or nasal, etc ...
- the useful dosage varies according to the age and weight of the patient, the route of administration, the nature and the severity of the condition and the taking of any associated treatments and ranges from 0.5 mg to 500 mg in one or more doses per day.
- the starting materials used are known products or prepared according to methods known operating procedures.
- Example 1 6-Hydroxy-3,3-dimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one.
- Example 4 0.33 g of the product of Example 4 is added to a cooled solution of 0.82 ml of pyridine and 0.82 ml of acetic anhydride. After 6 days at room temperature, the reaction medium is poured onto ice. . A precipitate is formed which is filtered, washed with water and then dried under vacuum. 0.36 g of the expected product is obtained. Melting point: 163 ° C.
- Example 7 cis -7-Methoxy-4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4.5] pyrano [3,2-h] acridin-2,8-dione
- Example 8 6- (Dimethylaminoethylamino) -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 11 6 - [(3-Morpholine-4-yl) propylaminol-3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 12 6 - [(2-Morpholine-4-yl) ethylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
- Example 13 6 - [(2-Piperidine-1-yl) ethylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
- Example 4 The procedure is as in Example 4, using the compound of Example 8 as the substrate.
- Example 16 ( ⁇ ) - cis -9-Methoxy-6,6,17-trimethyl-3,4,5a, 10,17,17c-hexahydro-2H, 6H-benzo [b] [1,4] dioxepino [ 2 ', 3': 4,5] pyrano [3,2-h] acridin-2,4,10-trione
- Example 5 The procedure is as in Example 5, using the compound of Example 4 as the substrate. and as a reagent acylmalonic dichloride.
- Example 17 cis -7- (Dimethylaminoethylamino) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4, 5] pyrano [3,2-h] acridin-2,8-dione
- Example 21 ( ⁇ ) - cis -1-Acetoxy-2-benzoyloxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2 -h] acridin-7-one.
- Step 1 ( ⁇ ) -1-Azido-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one
- Step 2 ( ⁇ ) -1-Amino-2-hydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one.
- Example 23 7-Methoxy-4,4,15-trimethyl-1,3a, 4,8,15,15c-hexahydro-2H-benzo [b] [1,3] oxazolo [4 ', 5': 4, 5] pyrano [3,2-h] acridine-2,8-dione
- Example 28 6 - [(2-Morpholine-4-yl) ethyloxy] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7- one
- Example 31 6 - [(Carbomethoxy) propylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 32 6 - [(Carbomethoxy) butylamino] -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 33 cis -6- (Dimethylaminopropylamino) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 4 The procedure is as in Example 4, using the compound of Example 9 as the substrate.
- Example 34 cis -6 - [(2-Morpholin-4-yl) ethylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 35 cis -6 - [(2-Piperidin-1-yl) ethylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 36 trans -6- (Dimethylaminoethylamino) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 37 cis -6- (Dimethylaminoethyloxy) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 38 cis -6- (Dimethylaminopropyloxy) -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 39 cis- 6 - [(2-Morpholine-4-yl) ethyloxy] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 40 cis -6 - [(Carbomethoxy) methylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
- Example 41 cis -6 - [(Carbomethoxy) propylamino] -1,2-dihydroxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
- Example 42 cis -1,2-Diacetoxy-6- (dimethylaminopropylamino) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 43 cis -1,2-Diacetoxy-6 - [(2-morpholine-4-yl) ethylamino] -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 46 cis -1,2-Diacetoxy-6- (dimethylaminoethyloxy) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 47 cis -1,2-Diacetoxy-6- (dimethylaminopropyloxy) -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin -7-one
- Example 48 cis -1,2-Diacetoxy-6 - [(carbomethoxy) methylamino] -3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2- h] acridin-7-one
- Example 49 cis -1,2-Diacetoxy-6 [(carbomethoxy) propylamino] -3,3,14-trimethyl-2,3,7,14-tetrahdyro-1H-benzo [b] pyrano [3,2-h ] acridin-7-one
- Example 50 cis -7- (Dimethylaminopropylamino) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo- [4 ', 5': 4 , 5] pyrano [3,2-h] acridin-2,8 -dione
- Example 51 cis -6 - [(2-Morpholine-4-yl) ethylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4.5] pyrano [3,2-h] acridin-2,8 -dione
- Example 52 cis -6 - [(2-Piperidine-1-yl) ethylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4,5] pyrano [3,2-h] acridin-2,8-dione
- Example 53 cis -6- (Dimethylaminoethyloxy) -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4, 5] pyrano [3,2-h] acridin-2,8-dione
- Example 54 cis -6 - [(Carbomethoxy) propylamino] -4,4,15-trimethyl-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5' : 4,5] pyrano [3,2-h] acridin-2,8-dione
- Example 55 cis -7-Methoxy-4,4,15-trimethyl-2-thioxo-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5': 4,5] pyrano [3,2-h] acridin-8-one
- Example 56 cis -7- (Dimethylaminoethylamino) -4,4,15-trimethyl-2-thioxo-3a, 8,15,15c-tetrahydro-4H-benzo [b] [1,3] dioxolo [4 ', 5 ': 4,5] pyrano [3,2-h] acridin-8-one
- Example 55 The procedure is as in Example 55 using as substrate in the first step the composed of example 15.
- the product is isolated by chromatography on silica gel from Example 22 where it is forms as a co-product during the synthesis of this compound.
- Example 58 7-Methoxy-4,4,15-trimethyl-1,2,3,3a, 4,8,15,15c-octahydro-benzo [b] imidazo [4 ', 5': 4,5] pyrano [3,2-h] acridin-2,8-dione
- Example 57 The compound of Example 57 is treated according to the conditions described in Tetrahedron. Lett. 1974, 1191.
- Example 60 9-Methoxy-6,6,17-trimethyl-1,3,4,5a, 6,10,17,17c-octahydro-2H-benzo [b] [1,4] oxazepino [3 ', 2 ': 4,5] pyrano [3,2-h] acridin-2,4,10-trione
- Example 2 The procedure is as in Example 2, using the compound of Example 61.
- Example 63 cis -10.11-Dichloro-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2 -h] acridin-7-one
- Example 4 The procedure is as in Example 4, using the compound of Example 62.
- Example 2 The procedure is as in Example 2, using the compound of Example 66.
- Example 68 cis -10,11-Di -tert -butyl-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 4 The procedure is as in Example 4, using the compound of Example 67.
- Example 69 cis -1,2-Diacetoxy-10,11 - di- tert -butyl-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo [b] pyrano [3,2-h] acridin-7-one
- Example 5 The procedure is as in Example 5, using the compound of Example 68.
- Example 70 10,11-Di- tert -butyl-6- (dimethylaminoethylamino) -3,3,14-trimethyl-7,14-dihydro-3H-benzo [b] pyrano [3,2-h] acridin-7 -one
- Example 8 The procedure is as in Example 8, using the compound of Example 67.
- Murine leukemia L1210 has been used in vitro.
- the cells are cultured in complete RPMI 1640 culture medium containing 10% of fetal calf serum, 2 mM of glutamine, 50 U / ml of penicillin, 50 ⁇ g / ml of streptomycin and 10 mM of Hepes, pH: 7, 4.
- the cells are distributed in microplates and exposed to cytotoxic compounds for 4 doubling times, ie 48 hours. The number of viable cells is then quantified by a colorimetric test, the Microculture Tetrazolium Assay (J. Carmichael et al., Cancer Res., 47 , 936-942, (1987)).
- IC 50 a concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%.
- Table 1 Cytotoxicity for L 1210 cells in culture products Cytotoxicity IC 50 ( ⁇ M) Example 7 0,023 acronycine 27.0
- the P 388 line (murine leukemia) was supplied by the National Cancer Institute (Frederick, USA).
- the tumor cells (10 6 cells) were inoculated on day 0 in the peritoneal cavity of female B6D2F1 mice (Iffa Credo, France).
- Six mice weighing 18 to 20 g were used per experimental group.
- the products were administered intraperitoneally on day 1.
- Table 2 indicates the antitumor activity obtained at the optimal doses. Antitumor activity on the P 388 line Product Diagram way Optimal dose (mg / kg) T / C% Example 7 J1 ip 12.5 327 acronycine J1 ip 200 125
- Example 7 The product of Example 7 is very active in this model, whereas acronycin is only marginally active.
- the HT29 line was supplied by the ATCC (American Type Culture Collection, Rockville, USA).
- the tumor cells were inoculated into female Nude Swiss mice (10 7 cells per animal) subcutaneously. The tumors were then removed, dissociated into fragments which were grafted onto Nude mice subcutaneously. When the tumor volume reached 50 to 100 mm 3 , the mice were divided into experimental groups comprising 8 (control group) or 6 (treated groups) animals (day 0). The products were administered iv once a week for 3 weeks.
- V0 and Vt being respectively the initial volume and the volume at the measurement time t.
- Table 3 indicates the antitumor activity obtained at the optimal doses for Example 5: Antitumor activity on the HT29 line Product Diagram way Optimal Dose (mg / kg) T / C% at day 32 Example 5 D0, 7.14 iv 3.12 17
- Example 5 inhibits the growth of the HT29 tumor, which is general, not very sensitive to anti-tumor agents. This product is very active in this model, the inhibition being 83% on day 32, ie 18 days after the last administration.
- Preparation formula for 1000 tablets dosed at 10 mg Composed of Example 7 10 g Lactose 40 g Magnesium stearate 10 g Wheat starch 15g Corn starch 15g Silica 3 g hydroxypropyl 5 g
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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FR9716131A FR2772765B1 (fr) | 1997-12-19 | 1997-12-19 | Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR9716131 | 1997-12-19 | ||
PCT/FR1998/002785 WO1999032491A1 (fr) | 1997-12-19 | 1998-12-18 | Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Publications (2)
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EP1042326A1 EP1042326A1 (fr) | 2000-10-11 |
EP1042326B1 true EP1042326B1 (fr) | 2002-06-19 |
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EP98962511A Expired - Lifetime EP1042326B1 (fr) | 1997-12-19 | 1998-12-18 | Nouveaux derives de l'acronycine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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US (1) | US6288073B1 (xx) |
EP (1) | EP1042326B1 (xx) |
JP (1) | JP3825630B2 (xx) |
CN (1) | CN1109686C (xx) |
AT (1) | ATE219491T1 (xx) |
AU (1) | AU738322B2 (xx) |
BR (1) | BR9813756A (xx) |
CA (1) | CA2315909C (xx) |
DE (1) | DE69806189T2 (xx) |
DK (1) | DK1042326T3 (xx) |
ES (1) | ES2179548T3 (xx) |
FR (1) | FR2772765B1 (xx) |
HK (1) | HK1033131A1 (xx) |
HU (1) | HUP0100342A3 (xx) |
NO (1) | NO20003106L (xx) |
NZ (1) | NZ504833A (xx) |
PL (1) | PL192814B1 (xx) |
PT (1) | PT1042326E (xx) |
WO (1) | WO1999032491A1 (xx) |
ZA (1) | ZA9811645B (xx) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2795071B1 (fr) * | 1999-06-16 | 2001-07-27 | Adir | Nouveaux derives de carboxylate de 7-oxo-2,3,7,14- tetrahydro-1h-benzo[b]pyrano[3,2,h] acridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US7056929B2 (en) * | 2001-07-25 | 2006-06-06 | Les Laboratoires Servier | Benzo[b]pyrano[3,2-h]acridin-7-one compounds |
FR2827864B1 (fr) * | 2001-07-25 | 2005-09-16 | Servier Lab | Nouveaux derives de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2856687B1 (fr) * | 2003-06-25 | 2005-09-16 | Servier Lab | Nouveaux derives de benzo[a]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR2865734B1 (fr) * | 2004-02-03 | 2006-05-19 | Servier Lab | NOUVAEUX DERIVES DE BENZO[b]CHROMENO-NAPHTHYRIDIN-7-ONE ET DE PYRANO[2'3':7,8]QUINO[2,3-b]QUINOXALIN-7-ONE, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT |
FR2879600B1 (fr) * | 2004-12-22 | 2007-02-09 | Servier Lab | Nouveaux derives cinnamates de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
JP4392502B2 (ja) * | 2005-06-10 | 2010-01-06 | 国立大学法人 岡山大学 | 蛍光性アミノ酸誘導体 |
US11784731B2 (en) * | 2021-03-09 | 2023-10-10 | Apple Inc. | Multi-phase-level signaling to improve data bandwidth over lossy channels |
WO2024081561A2 (en) * | 2022-10-13 | 2024-04-18 | Siemens Healthcare Diagnostics Inc. | Acridinium compounds with fused heterocycles |
Family Cites Families (1)
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FR2716197B1 (fr) * | 1994-02-17 | 1996-04-19 | Adir | Nouveaux analogues de l'acronycine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
-
1997
- 1997-12-19 FR FR9716131A patent/FR2772765B1/fr not_active Expired - Fee Related
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1998
- 1998-12-18 HU HU0100342A patent/HUP0100342A3/hu unknown
- 1998-12-18 ZA ZA9811645A patent/ZA9811645B/xx unknown
- 1998-12-18 NZ NZ504833A patent/NZ504833A/en unknown
- 1998-12-18 JP JP2000525428A patent/JP3825630B2/ja not_active Expired - Fee Related
- 1998-12-18 US US09/581,853 patent/US6288073B1/en not_active Expired - Fee Related
- 1998-12-18 CA CA002315909A patent/CA2315909C/fr not_active Expired - Fee Related
- 1998-12-18 PT PT98962511T patent/PT1042326E/pt unknown
- 1998-12-18 EP EP98962511A patent/EP1042326B1/fr not_active Expired - Lifetime
- 1998-12-18 ES ES98962511T patent/ES2179548T3/es not_active Expired - Lifetime
- 1998-12-18 DE DE69806189T patent/DE69806189T2/de not_active Expired - Lifetime
- 1998-12-18 BR BR9813756-5A patent/BR9813756A/pt not_active Application Discontinuation
- 1998-12-18 DK DK98962511T patent/DK1042326T3/da active
- 1998-12-18 CN CN98812425A patent/CN1109686C/zh not_active Expired - Fee Related
- 1998-12-18 AT AT98962511T patent/ATE219491T1/de not_active IP Right Cessation
- 1998-12-18 AU AU17663/99A patent/AU738322B2/en not_active Ceased
- 1998-12-18 PL PL341281A patent/PL192814B1/pl not_active IP Right Cessation
- 1998-12-18 WO PCT/FR1998/002785 patent/WO1999032491A1/fr active IP Right Grant
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2000
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Also Published As
Publication number | Publication date |
---|---|
PL192814B1 (pl) | 2006-12-29 |
CA2315909A1 (fr) | 1999-07-01 |
PL341281A1 (en) | 2001-04-09 |
PT1042326E (pt) | 2002-10-31 |
FR2772765B1 (fr) | 2000-03-17 |
AU1766399A (en) | 1999-07-12 |
CN1109686C (zh) | 2003-05-28 |
ATE219491T1 (de) | 2002-07-15 |
CN1282332A (zh) | 2001-01-31 |
HUP0100342A2 (hu) | 2001-09-28 |
HK1033131A1 (en) | 2001-08-17 |
CA2315909C (fr) | 2007-01-02 |
US6288073B1 (en) | 2001-09-11 |
EP1042326A1 (fr) | 2000-10-11 |
JP3825630B2 (ja) | 2006-09-27 |
ES2179548T3 (es) | 2003-01-16 |
BR9813756A (pt) | 2000-10-03 |
HUP0100342A3 (en) | 2003-04-28 |
WO1999032491A1 (fr) | 1999-07-01 |
ZA9811645B (en) | 1999-06-24 |
NO20003106D0 (no) | 2000-06-16 |
DE69806189D1 (de) | 2002-07-25 |
NZ504833A (en) | 2001-11-30 |
AU738322B2 (en) | 2001-09-13 |
FR2772765A1 (fr) | 1999-06-25 |
NO20003106L (no) | 2000-08-16 |
DK1042326T3 (da) | 2002-09-23 |
DE69806189T2 (de) | 2003-02-13 |
JP2001526290A (ja) | 2001-12-18 |
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